Mutations in monoamine oxidase (MAO) genes in mice lead to hypersensitivity to serotonin-enhancing drugs: implications for drug side effects in humans

Fox, M. A.; Panessiti, M. G.; Moya, P. R.; Tolliver, T. J.; Chen, K.; Shih, J. C.; Murphy, D. L.


A possible side effect of serotonin-enhancing drugs is the serotonin syndrome, which can be lethal. Here we examined possible hypersensitivity to two such drugs, the serotonin precursor 5-hydroxy-L-tryptophan (5-HTP) and the atypical opioid tramadol, in mice lacking the genes for both monoamine oxidase A (MAOA) and MAOB. MAOA/B-knockout (KO) mice displayed baseline serotonin syndrome behaviors, and these behavioral responses were highly exaggerated following 5-HTP or tramadol versus baseline and wild-type (WT) littermates. Compared with MAOA/B-WT mice, baseline tissue serotonin levels were increased similar to 2.6-3.9-fold in MAOA/B-KO mice. Following 5-HTP, serotonin levels were further increased similar to 4.5-6.2-fold in MAOA/B-KO mice. These exaggerated responses are in line with the exaggerated responses following serotonin-enhancing drugs that we previously observed in mice lacking the serotonin transporter (SERT). These findings provide a second genetic mouse model suggestive of possible human vulnerability to the serotonin syndrome in individuals with lesser-expressing MAO or SERT polymorphisms that confer serotonergic system changes.

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Título según WOS: ID WOS:000327449700011 Not found in local WOS DB
Volumen: 13
Número: 6
Editorial: Nature Publishing Group
Fecha de publicación: 2013
Página de inicio: 551
Página final: 557


Notas: ISI